The relationship between cellular calcium (Ca) metabolism and systemic or skeletal homeostasis are poorly understood. We believe that the increasingly common, distinctive syndrome of familial benigh hypercalcemia (FBH, or hypocalciuric hypercalcemia) provides a unique opportunity for probing the mechanisms of Ca homeostasis. The FBH syndrome includes lifelong, dominantly-inherited hypercalcemia, enhanced renal tublar reabsorption of Ca, nonsuppressed but not elevated parathyroid hormone (PTH) secretion, generally normal parathyroid histology, and failure of subtotal parathyroidectomy to normalize serum Ca. Affected persons are frequently misdiagnosed as having primary hyperparathyroidism (1oHPT) and given inappropriate treatment. The central hypothesis of the proposed research is that FBH results from a pervasive, congenital alteration of cellular Ca metabolism, and thus differs fundamentally from 1oHPT in not having isolated hyperfunction of the parathyroids. The defect may be increased membrane Ca-Mg ATPase (Ca pump). More than 125 Mayo patients with FBH are available for study. We intend to determine 1) if there are characteristic abnormalities of cytosolic Ca ion levels or regulation, abnormal membrane CA pumping, or abnormal cytosolic Ca-binding proteins in FBH; 2) if intestinal absorption of Ca is enhanced as is renal tubular reabsorption of Ca; 3) whether renal responses to water deprivation and vasopressin administration are similarly altered in FBH and 1oHPT; 4) if FBH patients are hypersensitive to the effects of PTH; 5) if renal phosphorus handling, vitamin D activation, and plasma Ca are affected normally by phosphorus depletion and repletion; and 6) whether bone turnover is increased in FBH. Techniques to be used include in vitro assays of erythrocyte membrane Ca-Mg ATPase and 45Ca flux, measurement of cytosolic Ca ion levels and cytosolic Ca-binding proteins in cultured dermal fibroblasts, infusions of PTH or vasopressin, double isotope Ca absorption, PTH bioassay, assay of bone turnover markers, and bone histomorphometry. Expertise in all areas has been assured through appropriate coinvestigators and consultants. These comprehensive studies should improve knowledge of Ca homeostasis in general, help us to understand the pathogenesis of FBH, and could help in development of specific diagnostic tests for hypercalcemic patients.